Air Care Series: Calcium Channel Blocker Overdose
/HISTORY OF PRESENT ILLNESS:
The patient is a Fulani-speaking female in her 70s with a past medical history of hypertension and hyperlipidemia who presented to the emergency department (ED) after a non-intentional amlodipine overdose. The patient recently established care with a primary care provider and was prescribed amlodipine for her hypertension. Her daughter-in-law reviewed her medications and instructed the patient to take amlodipine once a day. Due to miscommunication/misinterpretation, the patient mistakenly ingested one entire bottle (300 mg). Once this ingestion was discovered, family members called EMS for evaluation and transportation to the hospital.
The patient arrived at the ED less than two hours from the time of her ingestion. Other than some mild nausea, the patient was feeling in her usual state of health.
Physical exam:
The patient was slightly anxious but nontoxic appearing and in no apparent distress. Her cardiopulmonary exam was unremarkable. Abdominal exam was soft and non-tender. Her extremities were warm and well perfused with palpable peripheral pulses.
Labs:
WBC – 17.1 Hgb – 11.1
Sodium 130, Potassium 4.3, Chloride 98, Bicarb 17,Glucose 181, BUN 46, Creatinine 1.74, Calcium 9.3, Magnesium 2.2
Total Protein 7.8, AST 47 , ALT 40, Total Bilirubin 0.7
Ethanol <10, Acetaminophen <10, Salicylate < 3
Hs-Troponin 33
Past History:
hypertension, hyperlipidemia
Medications:
amlodipine, atorvastatin, losartan
Vitals:
BP 127/48 mmHg HR 84 bpm RR 22 breaths/min Oxygen Saturation 91% on room air Temp 98.1 F
EKG:
Sinus Rhythm at a rate of 88 beats per minute. Slight QTc prolongation of 493 without evidence of QRS widening. No ST-segment changes.
Echo:
hyperdynamic left ventricle with a small left ventricle caliber and collapsible IVC
Hospital course:
Upon arrival to the ED, the patient was given activated charcoal for her recent overdose. The MICU was notified about the patient and accepted the patient under their service. Before departing the ED, the patient became hypotensive despite fluid resuscitation, and was started on a peripheral norepinephrine drip. Shortly after arriving to the MICU, the patient became altered and was intubated for airway protection. Her hypotension continued to worsen, so vasopressin and epinephrine were added for hemodynamic support. Additional therapies were started including high dose insulin therapy, lipid emulsion, therapy, calcium gluconate drip, and a glucagon drip. Despite these measures, the patient had a refractory acidosis and progressive oliguria, necessitating CRRT. The patient continued to decline requiring methylene blue for refractory hypotension. Plasma exchange therapy was considered, but the patient suffered an asystolic arrest, presumably due to her worsening hypotension and hypoxemia. Resuscitation with standard ACLS measures occurred, but the team was unable to obtain ROSC. She was pronounced dead less than 24 hours into her hospital stay, 25 hours from the time of her ingestion.
Discussion:
This case highlights the difficulties providers encounter with ingestions of dihydropyridine calcium channel blockers, specifically amlodipine. These overdoses present with vasodilatory shock, ultimately leading to cardiovascular collapse. Resuscitative efforts are aimed at counteracting the effects of the medication. In the following sections, we will review the offending agent’s unique characteristics, standard medical therapies, and rescue therapies in patients who are refractory to medical treatments.
Pharmaco-kinetics & dynamics
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the influx of calcium in the peripheral and coronary vasculature resulting in vasodilation. This inhibition occurs as L-type calcium channels are blocked. Toxic levels of amlodipine create the overdose’s specific findings due to the end-organ effects on the heart, blood vessels, and pancreas. Amlodipine is slowly and almost wholly absorbed after oral administration, and it has an oral bioavailability of 60-65%.[1] Peak plasma concentrations are attained within 6-12 hours, and its half-life is about 35-45 hours.[1] Absorption is not influenced by food, and both its bioavailability and half-life appear to be increased in the elderly population.[2] Amlodipine has a large volume of distribution of 21 L/kg, and more than 95% of the drug is bound to plasma protein.
The Resuscitation:
The Resuscitation for CCB can generally be thought of as occurring in three simultaneous categories: reduction of the CCB effect, circumventing their MOA, and removal of the CCB. The medications and interventions used during resuscitation often blur the lines between these categories. These medications’ efficacy has not been proven with large trials but is based on the best-case available series data, animal trials, and pathophysiologic mechanisms.
Gastric Decontamination
The goal of gastric decontamination is to prevent further systemic absorption of an ingested substance. Decreased absorption is achieved through various means that can include activated charcoal, gastric lavage, and whole bowel irrigation. While the utility of gastric decontamination is debated and systematic reviews have found a low level of evidence supporting its use3, there have been documented case reports of its utility, with many authors supporting its use in the proper clinical setting.
Activated charcoal works by lining the intestinal tract to decrease systemic absorption of potentially toxic substances and is most effective if used within the first 1-2 hours of ingestion.[4,5] The time-dependent nature of activated charcoal was demonstrated in a study by Laine et al. A group of healthy individuals was given 10 mg of amlodipine followed by activated charcoal at different times after the ingestion. Based on drug levels obtained via blood and urine over four days, they found that activated charcoal was most effective immediately after ingestion (reduced area under the curve of amlodipine by 99%) with continued benefit if given 2 hours after ingestion (reduced area under the curve of amlodipine by 49%). After 6 hours, activated charcoal showed a minimal reduction of absorption and did not affect half-life. The recommended dose is 1g/kg, with 50g being an effective first dose for most overdoses.[6,7] Activated charcoal should be used with caution in those with an altered level of consciousness or those who are unable to maintain their airway as it may provoke emesis and lead to aspiration.
Gastric lavage is a technique used to empty the stomach of toxic substances that involves the placement of a large-bore tube with subsequent administration and aspiration of fluid. While once widely used, it has fallen out of favor due to the lack of efficacy and increased risk of complications.[3] Gastric lavage can be considered in patients presenting within 1 hour of ingestion, with a possible extension of up to 2 hours pending the clinical scenario. Intubation should strongly be considered prior to the procedure, given the large bore tube used and the increased risk of aspiration. Multiple doses of charcoal should be given during the procedure to help prevent increased delivery of the toxic substance to the small bowel. The gastric lavage process is typically initiated by starting with a dose of charcoal, then performing the lavage, followed by administering additional doses of charcoal. Specific considerations for gastric lavage should be made in those presenting with amlodipine overdose as the increased vagal tone from the passage of the large bore tube in the esophagus combined with the effects of the calcium channel blocker (bradycardia, decreased cardiac contractility, and decreased systemic vascular resistance) can lead to cardiovascular collapse.[7]
Whole bowel irrigation is used to prevent continued absorption of a toxic substance from the gastrointestinal tract by mechanically flushing the substance out of the body. Irrigation is typically accomplished by continuous administration of polyethylene glycol by mouth or via NG tube at a rate of about 2L per hour until bowel movements become clear. This technique can be considered in patients who ingested a sustained released preparation of amlodipine.[5,7] As with activated charcoal and gastric lavage, caution must be used in those with an altered level of consciousness or those who are unable to protect their airway.
Initial pharmacotherapy
Glucagon While there may be some data to support glucagon in beta-blocker overdoses, the data on its use in calcium channel blocker overdoses has been lackluster to date. While some authors suggest it may work by activating L-type calcium channels through an alternative mechanism, others have found no clinical benefit and do not universally recommend its use.[4,5,7] Additionally, a systematic review found no relevant human studies and was limited to only animal modules that found no effect on mean arterial pressure or overall survival.8 If used, dosing typically begins with 5-10 mg intermittent boluses followed by a continuous infusion of 5-10 mg/hr if a response is noted.
Atropine may help increase heart rate in mild to moderate overdoses but is unlikely to be helpful in severe overdoses and has the potential to worsen bradycardia in patients with a conduction disturbance.[5,7] Atropine can be administered as 0.5-1.0 mg IV boluses every two to three minutes for a maximum of 3 mg.
Calcium is theorized to increase the extracellular calcium concentration to drive an influx of calcium to unblocked L-type calcium channels.[5] Once bound, it may help improve inotropy and blood pressure. There is mixed data on its efficacy, but given its availability and overall favorable safety profile, it is recommended to administer either calcium gluconate (via peripheral IV) or calcium chloride (via central access) until calcium levels near the upper limit of normal or are slightly above normal.[5,7]
Vasopressors Norepinephrine is a balanced vasopressor with both alpha and beta activity. Its vasoconstrictive and inotropic effects make it the preferred first-line agent in amlodipine overdoses.[4] Patients with a significant overdose may need high doses to maintain an appropriate mean arterial pressure. If an adequate response is not achieved with norepinephrine monotherapy, additional agents such as epinephrine, vasopressin, and phenylephrine can be added.
High dose insulin (HDI) therapy for the treatment of calcium channel blockers has been around for decades, with its first documented use in the late 1990s. Since then, its popularity has increased as more and more case reports describe its effectiveness in helping treat these overdoses.[9,10]
The exact mechanism behind HDI therapy is still unknown. Under normal physiologic conditions, myocardial cells utilize free fatty acids as their primary source of energy. However, under stress (such as poor hemodynamics), myocardial cells begin to favor glucose as their energy source. Through amlodipine’s action on L-type calcium channels, insulin release by pancreatic B-islet cells and glucose uptake by the tissues is impaired. This creates a state of hypoinsulinemia, and relative insulin resistance is thought to contribute to the pathophysiology of calcium channel blocker cardiovascular toxicity as the uptake of glucose by the myocardial and vascular muscle cells is inhibited.[9] The lack of fuel and energy stores further compromises the cardiovascular condition already impaired by amlodipine. In part, HDI is theorized to work by breaking this cycle to help improve inotropy and vascular tone.[4,9,10]
HDI involves a loading dose of 1 unit/kg of regular insulin followed by an infusion of 0.5-2 units/kg/hr. Based on case reports, this therapy seems most effective when initiated early in the patient’s presentation and could have reduced clinical benefit when initiated as rescue therapy.[9,10] HDI therapy is continued until there is a good clinical response (such as improved hemodynamics and acidosis). While these doses of insulin are considered high-risk therapy, it has been proven to have an overall good safety profile when used in the appropriate clinical setting. Greene et al. helped establish this when they did a prospective observational study in 7 critically ill patients with significant calcium channel blocker overdose (defined as SBP <90) and found no clinically significant adverse effects. These patients do require careful monitoring as hypoglycemia and electrolyte derangements (hypokalemia, hypomagnesemia, hypophosphatemia) can occur.[3,11]
Intravenous Lipid Emulsion therapy (ILE) therapy is thought to work in calcium channel blocker overdose in three ways: formation of a lipid sink that traps molecules in the lipid partition of the plasma that prevents its downstream effects, the direct energy source to myocardiocytes in the form of free fatty acids, and direct stimulation of the L-type calcium channels.[4,12] There have been case reports documenting its utility in amlodipine overdoses as patients who were given ILE early in their clinical course showed rapid improvement to their hemodynamics, sometimes without the initiation of other common treatments such as HDI.[4,13] Dosing is based on the literature for its use in other indications such as local anesthetic systemic toxicity. It is recommended to start with a 1.5 ml/kg bolus of 20% lipid emulsion (can be repeated if persistent cardiovascular collapse is evident) followed by a 0.25 - 0.5 ml/kg/min infusion over 30-60 minutes.[4,13] Labs should be drawn before administration as it can affect results. Adverse effects associated with ILE include pyrogenic reactions (fever, chills, myalgias), allergic reactions, fat overload syndrome (hyperlipidemia, hepatosplenomegaly, jaundice, fat embolism), and acute respiratory distress syndrome.[12,13]
Rescue Therapies
Extracorporeal Life Support (ECMO) has become an increasingly popular therapy over the past two decades. It has been used successfully to support patients for various pathologies such as severe acute respiratory distress syndrome, cardiopulmonary arrest, and overdoses. While the pathophysiology and mechanics behind ECMO are beyond the scope of this article, ECMO serves as a form of cardiopulmonary bypass to allow those with cardiovascular collapse to recover from the toxic effects of their ingestion. Several case reports have documented its success in helping patients with cardiovascular collapse due to overdoses recover without any adverse cardiovascular or neurological effects.[14,15,16] While early literature reviews showed mixed support on ECMO use in overdose, a large systematic review of therapies used in calcium channel blocker overdoses found that ECMO was only one of two therapies (with the other being HDI) that was supported by the strongest evidence. [17,18,3] ECMO is not a benign therapy as it is extremely invasive and is associated with significant adverse effects including limb ischemia, thrombosis, and hemorrhage.[3,17] As with any other intervention, it is crucial to select the appropriate patient population and weigh the therapy’s risks versus benefits.
Plasma Exchange Therapy (PLEX) involves separating the blood into plasma and cellular components by an automated device. The cells are returned to the patient while the plasma is removed and replaced with another fluid (typically albumin or fresh frozen plasma), thus removing the toxic substance from the patient.[19] It is best suited for large molecules, especially those located intravascularly, but small molecules that are highly protein-bound (like amlodipine) are often effectively removed.[15] According to the American Association of Blood Banks and the American Society of Apheresis, therapeutic plasma exchange for acute drug overdose is a Category II recommendation. It is considered an appropriate adjunctive treatment option.[15,19] It seems to be a suitable method for rapid drug elimination and case reports of patients with severe amlodipine overdose refractory to aggressive medical therapy have described its use in successfully decreasing the levels of amlodipine and improving the patients’ hemodynamics until full recovery is made.[16,19,20] It seems to be most effective when initiated early and has been used as adjunctive therapy with other rescue therapies such as ECMO.[15,16,19]
Other therapies
Multiple other therapies have been proposed to help combat the cardiovascular collapse associated with amlodipine overdose. Methylene blue is theorized to provide hemodynamic support by combating the nitric oxide (NO) induced vasodilation in amlodipine overdose by acting as a NO scavenger, preventing NO production, and impeding cGMP production.[20] While there have been reports of hemodynamic improvements in those with refractory shock, the overall evidence behind its benefit is sparse.[20,22,3,5] Other treatments that have been described but not well studied included sodium bicarbonate infusion (thought to work by correcting the acidosis that enhances calcium channel blocker binding to L-type calcium channels), phosphodiesterase III inhibitors, levosimendan, L-carnitine, and mechanical support with an intra-aortic balloon pump.[5,23] Overall, these modalities are not recommended as the evidence supporting them is lacking, but they can be considered as a last resort in those not responding to the therapies previously described above. Pacemakers can also be considered but often are of little utility as the overdose affects the myocytes themselves and not just the cardiac conduction system. This direct cellular gives transvenous or transcutaneous pacemakers little utility.
Summary
Due to its unique pharmacokinetics and pharmacodynamics, amlodipine ingestions are one of the most dangerous calcium channel blocker overdoses carrying an extremely high mortality rate. Patients require early, aggressive resuscitation to be offered the best chance of survival. While the quality of evidence regarding treatment modalities is lacking, consideration for HDI and ILE therapy should be made early. For patients with cardiovascular collapse, ECMO and PLEX should also be considered.
Authored BY Shawn Hassani, MD
Dr. Hassani is a PGY-3 in Emergency Medicine at the University of Cincinnati and soon to be critical care fellow at Washington University in St. Louis
Posted BY Chris Zalesky, MD MSc
Dr. Zalesky is a PGY-2 in Emergency Medicine at the University of Cincinnati
Faculty Editor Mel Otten, MD
Dr. Otten is a Professor of Emergency Medicine at the University of Cincinnati with expertise in Toxicology and Disaster Medicine
References:
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